The family of human heterodimeric integrin receptors consists of 24 members, which differ from each other in α and β subunits. Eight integrins of this superfamily (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, αβ1 and αIIbβ3) are able to recognize the RGD tripeptide fragment in natural and artificial ligands with varying activity and selectivity. The role of individual integrin subtypes and their cross-talks are only partially investigated due to lack of active and highly selective ligands, which are able to interact with only one single integrin subtype.
Nevertheless, already now the significance of distinct integrin subtypes in different diseases is established. That makes integrins of great interest from medical point of view. For example, integrin αvβ6 is used by the Foot-and-Mouth-Disease virus (FMDV) to enter host cells and is highly up-regulated in the course of multiple types of cancer and fibrosis.
Only few ligands are known so far that are highly active for αvβ6 integrin and at the same time possess no binding affinity toward other RGD-recognizing integrins. Unfortunately, their metabolic instability, their high molecular weight and the complexity of their structures limit their medical application.
It was shown that FMDV possesses the RXDLXXL(SEQ ID NO: 1) motif, which is responsible for selective interaction with αvβ6-integrin in an α-helical structure. Attempts to obtain selective αvβ6 ligands via incorporation of RXDLXXL (SEQ ID NO: 1) motif into cyclic peptides resulted in 10-12 mer peptides (WO 01/05810 by Merck-Serono). The best compound of this family, cyclo(RTDLdALR-Abu-Abu) (SEQ ID NO: 2), had an αvβ6 IC50 activity of ca. 1 nM. However, its selectivity against αvβ3 integrin was reported without exact values and the information about its selectivity against other integrin subtypes is completely missing.